Salva il tuo paziente settico! Importanza di una terapia

empirica precoce ed appropriata

Mario Venditti

Department of Public Health and Infectious Diseases

Policlinico Umberto I, “Sapienza” University of Rome

1

2

bacteriemia

fungemia

parasitemia

viremia

other

SIRS INFECTION

trauma

burns

pancreatitis

SEPSIS

others

Definitions

Comparison with other major diseases

†National Center for Health Statistics, 2001. §American Cancer Society, 2001. *American Heart

Association. 2000. ‡Angus DC et al. Crit Care Med. 2001;29(7):1303-1310.

Mo

rtali

ty

AIDS* Severe

Sepsis‡ AMI† Breast

Cancer§

Outcome of inadequate empirical antibiotic therapy in emergency department patients with community-onset BSIs

Hang Cheng C et al J Antmicrob Chemother 2013

30 day mortality HR (95%CI)

Uncomplicated

bacteremia (n=60) 0 -

Sepsis (n=480) 3.8% 2.81(1.03-7.65)

Severe sepsis (n=269) 32.0% 1.65(1.07-2.56)

Septic shock (n=128) 43.0% 1.07(0.61-1.87)

Adequate antibiotic was considered when active antibiotic was administered within 24 hours

Sepsis incidence and outcome: Contrasting the ICU with the hospital ward Esteban A et al, Crit Care Med 2007

Sepsis Severe Sepsis Septic Shock

Number 702 199 59

Incidence (x 100,000) 367 104 31

ICU admission % 12% 32% 75%

Out ICU mortality 36% 53.3%

In ICU mortality 11% 33%

ICU utilization and mortality

Courtesy of Viale PL

Università degli Studi di Udine – Clinica di Malattie Infettive

Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality Nguyen BH et al, +

Early Use of Polymyxin B Hemoperfusion in Abdominal Septic Shock The EUPHAS Randomized Controlled Trial

Cruz DN, Antonelli M, Fumagalli R, Foltran F, Brienza N, Donati A, Malcangi V, Petrini F, Volta G, Bobbio Pallavicini FM, Rottoli F, Giunta F, Ronco C

Relationship between the timing of administration of IgM and IgA enriched immunoglobulins in patients with severe sepsis and septic shock and the

outcome: A retrospective analysis Berlot G, Vassallo MC, Busetto N, Bianchi M, Zornada F, Rosato I, Tartamella F, Prisco L, Bigotto F, Bigolin T,

Ferluga M, Batticci I, Michelone E, Borelli M, Viviani M, Tomasini A.J

Crit Care. 2012 Apr;27(2):167-71.

Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in Patients With Septic ShockA Randomized Clinical Trial

Morelli M, Ertmer C, Westphal M, Rehberg S, , Kampmeier T, Ligges S,

Orecchioni A, D’Egidio A, D’Ippoliti F, Raffone, R, Venditti M, GuarracinoF,

Girardis M, Tritapepe L, PietropaoliP, Mebazaa A, Singer M

JAMA. 2013 Oct 23;310(16):1683-91

JAMA. 2009 Jun 17;301(23):2445-52

Effect of timing on survival

Crit Care Med 2006;34:1589-96

Time from hypotension onset (hours)

Frac

tio

n o

f to

tal p

atie

nts

GRAM – (47.9%):

• E. Coli

• Klebsiella spp

• Pseudomonas spp

Crit Care Med. 2006.

GRAM + (38%)

• S. aureus

• Streptococchi

• Enterococchi

• CONS

FUNGI (8.6%)

• Candida spp

• Aspergillus spp

Others (4.4%)

• Anaerobes

• Mycobacterium tubercolosis

Etiology of sepsis

MRSA VRE

MRConS S. pyogenes

FOUR FATAL CASES OF HEMORRHAGIC PNEUMONIAE DUE TO INVASIVE S.PYOGENES IN HEALTHY IMMUNOCOMPETENT INDIVIDUALS

Santagati M, Spanu T, Scillato M, Santangelo R, Cavallaro F, Arena V, Venditti M, Stefani S Emerg Infect Dis 2014

All strains were susceptible to the antibiotics tested and RM1, RMG1 and CT1 belonged to emm-type 1.0 while RMG2 was emm-type 3 …..sequence type (ST) analysis showed that RMG1 and CT1 belong to ST28 (CC28), while for RM1, we found a new single locus variant (slv) of ST28 designated ST648, finally RMG2 was ST15 (CC15) Taken together these data with the presence of the Sag profile does not explain the ability of one strain to determine this type of severe infection, it has been demonstrated that the expression of virulence genes changes based on environmental conditions such as during human infection This study highlights the unusual dissemination of invasive GAS and indicates the need to understand what host factors and/or strain virulence characteristics could be involve in severe invasive GAS infections so as to be helpful in therapeutic strategy.

CASO CLINICO

TERAPIA: antibiotici

+ fasciotomia

Uomo di 36 aa, affetto da LES in trattamento steroideo; si presenta con febbre elevata, dolore, eritema e tumefazione della gamba sinistra che procede rapidamente verso il ginocchio in 48 ore, e comparsa di grosse lesioni bollose blu. GB 7500, ptl 70.000 poi 15000. diagnosi presuntiva di fascite necrotizzante tipo I. Richiesta coltura di biopsia cutanea, emocolture TAS, ….

CASO CLINICO: fascite necrotizzante tipo II:

etiologia S. pyogenes

CA- MRSA

Antibiotics resistance rates of group A streptococci to erythro, azithro, and clinda between 2000 and 2012 at National Cheng Kung University Hospital in

Tainan City, Taiwan. Chuang et al Journal of Microbiology, Immunology and Infection (2013) early on line

Time–kill kinetics of oritavancin and comparator agents against S pyogenes Arhin et al International Journal of Antimicrobial Agents 34 (2009) 550–554

Minimo rilascio di mediatori di flogosi dopo esposizione di S. pneumoniae a daptomicina

Ceftriaxone

Daptomicina

2 ore dpo esposizione 6 ore dopo esposizione

Stucki A et al. Antimicrob Agents Chemother 2007;51:2249–2252

pneumococchi nel LCR dopo esposizione antibiotica

1. Malattia di base Diabete mellito

insufficienza renale acuta & dialisi lesioni cutanee

tossicodipendenza EV

2. Porta di accesso catetere vascolare

infezioni di cute e tessuti molli corpi estranei

infezioni ossa e articolazioni

S. aureus?

3. Presentazione clinica metastasi settiche

ascessi evoluzione necrotizzante

sepsi grave & shock settico

4. Microbiologia Cocchi Gram-positivi a grappolo

Sì!!

MRSA colonizzazione/ precedente infezione Prevalenza di MRSA >10% uno o più delle seguenti:

Ospedale o cronicario negli ultimi 6- 12 mesi Chinoloni o antibiotici ev negli ultimi 30 gg

>65 anni Emodialisi cronica

E’ possibile/probabile che si tratti di MRSA?

Vi era il sospetto di una grave infezione da S. aureus?

Mensa J et al. Rev Esp Quimioter 2008;21:234–258 Gemmell CG et al. J Antimicrob Chemother 2006;57:589–608 Falcone M, Serra P, Venditti M Eur J Intern Med,, 2009

MSSA

2

4

6

8

6 24 6 24

Controllo

Attività in vitro di diversi antibiotici vs MSSA and MRSA

ore ore

Daptomicina

Small, Chambers AAC 1990; 34:1227 La Plante, AAC 2004; 48:4665; Pace AAC 2003;47:3602

oxacillina

Vancomicina

Vancomicina

Daptomicina

Controllo

MRSA

Telavancina Telavancina

Linezolid, Tigeciclina Linezolid, Tigeciclina

Review: compilation of studies assessing the effects of inappropriate empirical antibiotic treatment for invasive MRSA infections (mainly bacteremia)

Paul M et al J Antimicrob Chemother 2010; 65: 2658–2665

ORs .1 indicate higher mortality with inappropriate empirical antibiotic treatment. Studies are subgrouped by performance of multivariable analysis and the event/covariate ratio in this analysis.

DAAT 2d not significant DAAT 1d significant

ISAC. International S aureus collaborative group. Retrospective analysis (2006-10) of 3394 episodes of MRSA BSI from Europe

and USA (ECCMID 2013)

% survival at day 14 day 90

median (range) 84(91 –78) 72(78-63)

Difference 12% 15%

Differences in mortality among 10 hospitals were significant after adjusting for age, MRSA, foci or

nosocomial acquisition

S1 vs S8 P=0.0001

Diagnostic strategies for rapid identification of MRSA BSIs at the Gemelli hospital

TTP, time to positivity; BSI, bloodstream infection ; ID, identification; AST, antimicrobial susceptibility testing

Automated instrument Blood cultures

Detection of positivity

Record TTP Time

010

20

30

40

50

Tim

e t

o g

row

th d

ete

ction (

hours

)

Enterococci Stafilococchi Streptococci Enterobacteriaceae Non fermenters

Culture-based methods

Gram staining

ID/ AST

Direct methods

Bruker BioTyper ID

AST Genomera

Time to positivity of microrganisms isolated in BSIs

hours GNB(n=4683) GP (3328) 7 8 Aeromonas Beta strept 9 Klebsiella, E coli 10 Enterobacter, Citrobacter S pneumoniae 11 Proteus, Acinetobacter S aureus 12 Salmonella alfa strept, Enterococcus 13 14 15 P aeruginosa 16 17 CoNs >20 H influenzae and NF-GNB

Soriano A. personal comunication 2013

Use of Antistaphylococcal b-Lactams to Increase DaptoActivity in Eradicating Persistent BSI aDue to MRSA: Role of Enhanced Dapto Binding

Dhand A et al CID 2011:53

Sinergismo dapto+oxacillina

dapto ++++++++++++++++++++

++++++++++++++++++++

Membrana cellulare stafilococcica

- - + - + - + - + - + - - - + - + - + - + - - + - ++++ - + - + - + - + - + ++ - + - ++ - + - +++++ - + - ++ + - + - + - + - + -

oxa oxa oxa

dapto

meropenem,

imipenem

ceftazidime, ceftriaxone

piperacillina ceftarolina

Confronto delle caratteristiche clinico-microbiologiche in 56 pazienti con sepsi da S. aureus con complicanze(53%)* o senza

complicanze(47%).II.

complicanze P si no gg a rx adeguato 2.5 1.1 < .03 febbre > 72 h 56% 33% gg batteriemia 3.6 1.5 < .01 shock settico 58% 3.7 < .002 polmonite batteriemica 17 0 < .03 * complicanze: 16 morti x infezione, 5 recidive, 12 metastasi settiche(6 endocarditi)

Falcone & Venditti, AIMI 2002

Minimo rilascio di mediatori di flogosi

dopo esposizione di S. aureus a daptomicina

0

10

20

30

40

TN

F, p

g/m

l (m

igli

aia

)

50

60

70

Isolato S1 Isolato S2

Oxacillina

Daptomicina

Vancomicina

Secrezione di TNF da cellule RAW 264.7 incubate con

ceppi di MSSA in presenza di antibiotici

* * *

*

* p<0.05

English BK et al. Antimicrob Agents Chemother 2006; Gerber P et al J Antimicrob Chemother, 2006

Determinants of mortality in patients

with severe infection

Vital organ invasion by

growing bacteria

Duplication time

30’

Host inflammatory

response

• Exoproteins

• CW components

(LPS, LT, etc..)

Early active antibiotic (PK/PD) To avoid

inflammatory

response

Bowker KE et al. J Antimicrob Chemother 2009;64:1044–1051

Bactericidal activity: daptomycin > vancomycin > teicoplanin

Daptomycin = 0.19 mg/l (6 mg/kg/24 h)

Vancomycin = 0.25 mg/l

(1 g/12 h)

Teicoplanin = 0.38 mg/l

(400 mg/24 h)

Time (hours)

Lo

g C

FU

/ml

0 6 12 18 24 30 36 42 48

2

3

4

5

6

7

8

9

Daptomycin retains potent bactericidal activity

against high-inoculum MRSA in vitro

P<0.01 77

0

20

40

60

80

100

<=1

era

dic

atio

n r

ate

, %

MIC predicts eradication rates in MRSA infections treated with vancomycin

71

1.5

21

2.0

Moise et al. Antimicrob Agents Chemother 2007; 51: 2582

Vancomycin MIC, µg/ml

The importance of a judicious and early empiric choice of antimicrobial for MRSA bacteraemia

Shime N et al Eur J Clin Microbiol Infect Dis (2010) 29:1475–1479

AUC/MIC >400 N(%) morti

entro 48 ore

18(37%) 1(6%)

mai o >48 ore

30(63%) 16(53%)

Relationship between the onset of treatment, 24-h vancomycin concentration and mortality

Thompson AH et al. J Antimicrob Agents 2009;63:1050–1057

1 g q12h (normal renal function)

* * * *

* * *

* * *

* *

Time after the start of therapy (hours)

Pre

dic

ted

co

nce

ntr

ati

on

(m

g/l

)

12 36 48 60 72 84 96 24

0

10

25

20

15

5

Distribution of vancomycin trough concentrations

over the first 4 days of therapy

Sepsis

Typical vancomycin dosing fails to achieve target

concentrations for sepsis even after 4 days

azione battericida rapida e concentrazione

dipendente di daptomicina vs S. aureus

Hawkey PM. J Antimicrob Chemother 2008:62 (Suppl 3):iii7–iii14

Lo

g10 C

FU

/ml

3

4

5

6

7

0 30 60 90 tempo, min

Controllo

Daptomicina (2× MIC)

Daptomicina (4× MIC)

Daptomicina (8× MIC)

40 30 20 10 0 15 5 25 35 0

20

40

60

80

100

120

Av

erag

e co

nce

ntr

ati

on

of

da

pto

my

cin

in s

eru

m,,µ

g/m

l

6 mg/kg in 30 minutes (n=15)

6 mg/kg in 2 minutes (n=15)

Time, h

Chakraborty A et al. J Antimicrob Chemother. 2009 Jul;64(1):151-8.

Single Dose

Similar PK profile of daptomycin with

intravenous infusion in 2 minutes Vs. 30 minutes

Azione battericida in vitro di daptomicina contro un alto

inoculum di cellule in fase stazionaria di MSSA

24 20 18 12 8 4 0 2 6 10 14 22 16

3

4

5

6

7

8

9

10

11

Lo

g1

0 C

FU

/ml

tempo, ore

Vancomicina

Daptomicina

Gentamicina

Ciprofloxacina

Controllo

Curve “Time–kill” contro MSSA in fase stazionaria

Concentrazioni

antibiotiche: 100 µg/ml

Nafcillina

Mascio CTM et al. Antimicrob Agents Chemother 2007;51:4255–4260

Clinical Practice Guidelines by the InfectiousDiseases Society of America

for the Treatment of MRSA Infections in Adults and Children Liu C et al Clin Infect Dis 2011;52(3):e18–e55

infezione antibiotico dose

adulti bambini

Batteriemia

vancomicina 15-20 mg/kg/8-12h 15mg/kg/6h

daptomicina 6(8-10)mg//kg/24h 8-10mg/kg/24h

Durata

- non complicata 2 settimane

- complicata 4-6 settimane

- endocardite su valvola nativa 6 settimane

Batteriemia e endocardite su valvola nativa

MRSA and MSSA Success at TOC: ITT Population

MRSA MSS

A

Su

cc

es

s, %

Daptomycin

Vancomyci

n Nafcillin 44.6 44.4

20

45

33

74

0

10

20

30

40

50

60

70

32.6

Difference in Success

Rtaes (95% CI):

11.9% (-8.3, 32.1)

14

43

46.7

Difference in Success

Rates (95% CI):

-2.1% (-19.0, 14.9)

28

60

Fowler et al. N Engl J Med. 2006;355:653-665.

Considerations for Higher Doses of Dapto in Critically ill Elderly Patients

with MRSA-BSI Falcone M, Russo A, Venditti M, Novelli A, Pai MP, Clin Infetc Dis, early on line, 2013

Histogram with kernel density overlay line plot of individual patient (n=50) dapto clearance

Considerations for Higher Doses of Dapto in Critically ill Elderly

Patients with MRSA-BSI Falcone M, Russo A, Venditti M, Novelli A, Pai MP, Clin Infetc Dis, early on line, 2013

Box and whisker plot of dapto AUC0-24 by the weight-based dose used in the population (n=50)

Comparison of clinical characteristics and outcomes of patients with augmented

dapto CL compared to those with normal CL Falcone M, Russo A, Venditti M, Novelli A, Pai MP, Clin Infect Dis, early on line, 2013

Cumulative fraction of response for three potential dapto AUC0-24 to MIC ratio targets and

probability of minimum concentrations (Cmin) above a threshold associated with skeletal

muscle toxicity for weight based and fixed dosing regimens in patients without sepsis Falcone M, Russo A, Venditti M, Novelli A, Pai MP, Clin Infect Dis, early on line, 2013

Cumulative fraction of response for three potential dapto AUC0-24 to MIC ratio targets and

probability of minimum concentrations (Cmin) above a threshold associated with skeletal

muscle toxicity for weight based and fixed dosing regimens in patients with sepsis Falcone M, Russo A, Venditti M, Novelli A, Pai MP, Clin Infect Dis, early on line, 2013

1. Vidaillac C et al. Antimicrob Agents Chemother 2011;55:2160–2165

2. Novartis Europharm Ltd. Cubicin (daptomycin) Summary of Product Characteristics. 2011

Growth control

Time (hours)

Log

10 C

FU

/g o

f si

mu

late

d

end

oca

rdia

l v

eget

atio

n

0

4

8

24

32

48

56

72

19

2

16

8

15

2

14

4

12

8

12

0

96

1

00

1

04

1

3

5

7

9

11

Time of escalation/de-escalation

Daptomycin activity against high inoculum clinical MRSA isolates in vitro1

DAP 6 mg/kg

DAP 610 mg/kg

DAP 106 mg/kg

DAP 10 mg/kg

Refer to the daptomycin Summary of Product Characteristics for dosing recommendations2

Support for initial high dose daptomycin followed by dose de-escalation

GRAM – (47.9%):

• E. Coli

• Klebsiella spp

• Pseudomonas spp

Crit Care Med. 2006.

GRAM + (38%)

• S. aureus

• Streptococchi

• Enterococchi

• CONS

FUNGI (8.6%)

• Candida spp

• Aspergillus spp

Others (4.4%)

• Anaerobes

• Mycobacterium tubercolosis

Etiology of sepsis

MDR

Fattori di rischio

BGN MDR

K. Pneumoniae KPC

• Colonizzazione

• Charlson Index ≥3

• CVC

• Chirurgia recente

• Neutropenia

• ≥ 2 recenti ospedalizzazioni

• Tp antibiotica:

- fluorochinoloni

- carbapenemi

47

A. baumannii • Precedente

infezione/colonizzazione • Durata degenza • Chirurgia recente • CVC • NPT • Ventilazione meccanica • Tp antibiotica: - carbapenemi - pip/tazo - cefalosporine IV

Multivariate analysis of risk factors for inhospital

mortality in patients with infection due to CR-KP*

OR(95% CI) P

COPD 8.98(2.09-38.59) 0.003

Hosp. in ICU 15.76(33.35-74.10) <0.001

BSI 11.42(2.68-48.63) 0.001

Colistin-R KP 5.54(1.40-21.91) 0.01

High rate of colistin resistance among patients with carbapenem-resistant

Klebsiella pneumoniae infection accounts for an excess of mortality Capone A, Giannella M, Venditti M, Tarasi A, …Carattoli A, Petrosillo & SEERBIO-GRAB network, Clin Microbiol Infection, 2012

• Inter-hospital spread (7 roman hospitals) of two major clones, ST512 and ST258.

• 36.1% and 20.4% of strains were also resistant to colistin and tigecycline, respectively

•infection was diagnosed in 91 patients who received appropriate antibiotic treatment and combination

therapy, in 73.6% and 59.3%, respectively

•Inhospital mortality was 25%

* Adjusted for appropriate antibiotic therapy, combination therapy and removal of the

infectious source

Successful Ertapenem-Doripenem Combination Treatment of Bacteremic VAP due to Colistin-Resistant

KPC-Producing Klebsiella pneumoniae Ceccarelli G, Falcone M, Giordano A, Mezzatesta ML, Caio C, Stefani S & Venditti M Antimicrob Agents Chemother 2013

Sinergismo

colistina +ertapenem +meropenem +

gentamicina

GRAM – (47.9%):

• E. Coli

• Klebsiella spp

• Pseudomonas spp

Crit Care Med. 2006.

GRAM + (38%)

• S. aureus

• Streptococchi

• Enterococchi

• CONS

FUNGI (8.6%)

• Candida spp

• Aspergillus spp

Others (4.4%)

• Anaerobes

• Mycobacterium tubercolosis

Etiology of sepsis

Fattori di rischio

C. difficile • Pregressa Tp antibiotica

- fluorochinoloni; cefalosporine III

• Precedente episodio di CDI

• Età

• Durata degenza

Ribotipo 027 associato a rischio maggiore di complicanze

(Shock settico/megacolon tossico) 52

Casi di infezione da C. difficile in un ospedale di Roma

Guastalegname M,Grieco S,Giuliano S,Falcone M,Caccese R…,Venditti M. Infection 2014 (IN PRESS)

A cluster of fulminant C. difficile colitis in an Intensive Care Unit in Italy Guastalegname M,Grieco S,Giuliano S,Falcone M,Caccese R…,Venditti M. Infection 2014

C difficile & surgery

Indications, timing and …..

• Megacolon

• Colonic perforation

• Acute abdomen

• Septic shock (selected cases)

• Emergency colectomy for fulminant CDI caused

by ribotype 027: mostly beneficial in pts with age

> 65 years, immunocompetent, WBC> 20.000

cmm, lactate 2,2-4,9 mmol/l *

*Lamontagne F. et al. Ann Surg 2007; 245: 267-72

Courtesy of F Menichetti

Impact of Emergency Colectomy on Survival of Pts With Fulminant CDAD

During an Epidemic Caused by a Hypervirulent Strain

Colectomy Died/total unadjusted OR) addjusted OR

(95%CI) (95%CI)

No 74/127 (58%) 1.0 1.0

Yes 13/38 (34%) 0.4(0.2-0.8)* 0.2(0.1-0.7)*

* p<0.05

Lamontagne, Ann Surg 2007

Diverting Loop Ileostomy and Colonic Lavage

An Alternative to Total Abdominal Colectomy for the Treatment of Severe,

Complicated Clostridium difficile Associated Disease

Neal M et al . Annals of Surgery r 254: 423, 2011

Ribotype 027 C. difficile colitis and candidemia: is there the link!!

Variables Candida-/Clostridium +

n= 19

Candida-/Clostridium +

n= 60

p

Age years 76 75.8 years n.s.

Sex male 10 (52.6%) 34 (56.6%) n.s

Time at risk for clostridium infection

(days)

12.2 13.1 n.s.

Severe CDI infection 19 (100%) 26 (43.3%) <0.001

CDI relapse 15 (78.9%) 14 (23.3%) <0.001

CDI Relapse (days) 21.7 34.1 <0.001

Ribotype 027 15 (78.9%) 8 (13.3%) <0.001

Time at risk for candidemia (days) 20.1 - <0.001

Candidemia risk factors 9 (47.3%) 19 (31.6%) 0.03

Candida score 1.7 1.4 n.s.

Previous antibiotic therapy 19 (100%) 32 (53.3%) <0.001

Previous antifungal therapy 4 (21%) 4 (6.6%) <0.001

Presence of at least 2 comorbidities 19 (100%) 43 (71.6%) 0.02

Transfer to ICU 4 (21%) 10 (16.6%) 0.02

Days of ICU stay 12.1 13.4 n.s.

Days of hospital stay 48.2 31.2 <0.001

SOFA score median 3.8 1.9 <0.001

Severe sepsis or Septic shock 14 (73.6%) 15 (25%) <0.001

Dead 11 (57.8%) 15 (25%) <0.001

GRAM – (47.9%):

• E. Coli

• Klebsiella spp

• Pseudomonas spp

Crit Care Med. 2006.

GRAM + (38%)

• S. aureus

• Streptococchi

• Enterococchi

• CONS

FUNGI (8.6%)

• Candida spp

• Aspergillus spp

Others (4.4%)

• Anaerobes

• Mycobacterium tubercolosis

Etiology of sepsis

Fattori di rischio

Candida spp. • Terapia antibiotica

• Colonizzazione da Candida spp.

• CVC

• NPT

• Terapia steroidea

• Neoplasia

• DM

• Età

• Pazienti chirurgici:

• - Trapianto

• - Cardiochirurgia

• - Chirurgia addominale 60

61 Clin Infect Dis 2012; 54:1739-46

62 Clin Infect Dis 2012; 54:1739-46

Some reflections……

• Survivors 69 - Deaths 155

• Delayed therapy (after 24 h from blood culture positivity): 44 patients

• Out of these 44 patients, 41 did not receive any antifungal therapy because blood cultures became positive post mortem…….

• Importance of early diagnosis!

A multicenter study of septic shock due to candidemia: outcomes and predictors of mortality

Bassetti M et al Intensive Care Med 2014

63

retrospective study in which patients with septic shock attributable to Candida who were treated during the 3-year study period at one or more of the five participating teaching hospitals in Italy and Spain (N=216)

A multicenter study of septic shock due to candidemia: outcomes and predictors of mortality

Bassetti M et al Intensive Care Med 2014

64

retrospective study in which patients with septic shock attributable to Candida who were treated during the 3-year study period at one or more of the five participating teaching hospitals in Italy and Spain (N=216)

A multicenter study of septic shock due to candidemia: outcomes and predictors of mortality

Bassetti M et al Intensive Care Med 2014

65

Multivariate analysis of risk factors for 30 day hospital mortality

Nuovi fattori di rischio

….. A parte la granulocitopenia grave persitente da citostatici!

Epatopatia grave (Child-Pugh C)

BPCO

Trattamento corticosteroideo prolungato

PREDICTORS OF MORTALITY IN NONNEUTROPENIC PATIENTS WITH INVASIVE PULMONARY ASPERGILLOSIS (IPA): DOES

GALACTOMANNAN HAVE A ROLE? Russo A, Giuliano S, Vena A, Falcone M, Lucidi C, Merli M & Venditti M Diagn Microbiol Infect Dis, in press 2014

Number (%) of patients Variable Survivors Nonsurvivors P RR (95% CI)

(n=17) (n=7)

Cirrhosis 1 (5.9) 6 (85.7) >.01 1.45 (2.12-100) Voriconazole 15 (88.2) 2 (28.6) >.01 .17 (.04-.66) GM index (mean ± SD) 1.9 ± .6 3.6 ± 2.8 .02 …

Not significant variables: age, sex, steroid & immunosuppressive therapy, other comorbidities

(hematologic malignancies, solid tumor, BPCO, HIV infection…), presence of fever or leukocytosis, concomitant antibiotic therapy…

Univariate analysis of factors associated with death among patients with IPA.

deaths cirrhosis vs non cirrhosis:

6% vs 87%

Mechanisms of action

Ungerminated conidia of Aspergillus funigatus were insensitive to amphotericin B methyl ester (AME) at concentrations > 50 ,ug/ml, but rapidly became sensitive to I to 2,ugAME/ml during the initial stages

of germination. Relationship with sterol metabolism during germination of conidia….. Russell B et al Journal of’GeneraI MicrobioIogy (1977), 101, 197-206

Caspofungin versus Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Persistent Fever and Neutropenia

Walsh T et al N Engl J Med 2004;351:1391-402

Tassi di risposta nelle infezioni fungine documentate al «basale» (cioè entro 48 h dall’inizio dell’antifungino)

caspo Ampho B

conclusioni

Salvare il paziente settico richiede (a parte le terapie non strettamente antimicrobiche)….

1. Conoscenza dei fattori di rischio ed epidemiologie locali per anticipare la possibile etiologia….

2. Per mettere in atto un trattamento adeguato precoce che è fondamentale per la «salvezza»…

3. …. Rivalutare e studiare varie forme di terapia combinata antimicrobica….

4. …. Molte sepsi sono superfinfezioni in corso di trattamento antimicrobico che forse oggi dobbiamo imparare a prevedere ed evitare… o riconoscere più tempestivamente (esempio candidemia in corso di C difficile, ……. O lo stesso C difficile …..)

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